6-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-N-isopropyl-N'-(2-methoxy-4-methyl-phenyl)-[1,3,5]triazine-2,4-diamine pentahydrochloride

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 6-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-N-isopropyl-N'-(2-methoxy-4-methyl-phenyl)-[1,3,5]triazine-2,4-diamine pentahydrochloride
• 英文别名: 6-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]-4-N-(2-methoxy-4-methylphenyl)-2-N-propan-2-yl-1,3,5-triazine-2,4-diamine;hydrochloride
• 化学式: C₂₂H₃₆N₈O*5ClH
• 分子量: 610.886
• InChiKey: SQRYWAFJFSGGGR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.86
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  81.7
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-甲氧基-4-甲基苯胺 在 盐酸 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 5.0h， 生成 6-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-N-isopropyl-N'-(2-methoxy-4-methyl-phenyl)-[1,3,5]triazine-2,4-diamine pentahydrochloride
  参考文献：
  名称：

  Elaborate ligand-based modeling and subsequent synthetic exploration unveil new nanomolar Ca2+/calmodulin-dependent protein kinase II inhibitory leads

  摘要：

  Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been recently implicated in cardiovascular diseases and hypertension prompting several attempts to discover and optimize new CaMKII delta inhibitors. Towards this end we explored the pharmacophoric space of 88 CaMKII delta inhibitors using nine diverse sets of inhibitors to identify high quality pharmacophores. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing self-consistent quantitative structure-activity relationship (QSAR) of optimal predictive potential (r(72)(2) = 0.70, F = 18.19, r(LOO)(2) 0.71, r(PRESS)(2) against 16 external test inhibitors = 0.60). Three orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least three binding modes accessible to ligands within CaMKII delta binding pocket. Receiver operating characteristic (ROC) curves analysis established the validity of QSAR-selected pharmacophores. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute (NCI) list of compounds. In silico screening identified nanomolar and low micromolar inhibitors. The most potent hits exhibited IC50 values of 20 and 82 nM. The best pharmacophoric model (Hypo8/31) was employed to guide the synthesis of novel triazine-based CaMKII delta inhibitors, of which the most potent illustrated an IC50 value of 154 nM against CaMKII delta. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.10.071

文献信息

• Elaborate ligand-based modeling and subsequent synthetic exploration unveil new nanomolar Ca2+/calmodulin-dependent protein kinase II inhibitory leads
  作者：Rand Shahin、Mutasem O. Taha

  DOI：10.1016/j.bmc.2011.10.071

  日期：2012.1

  Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been recently implicated in cardiovascular diseases and hypertension prompting several attempts to discover and optimize new CaMKII delta inhibitors. Towards this end we explored the pharmacophoric space of 88 CaMKII delta inhibitors using nine diverse sets of inhibitors to identify high quality pharmacophores. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing self-consistent quantitative structure-activity relationship (QSAR) of optimal predictive potential (r(72)(2) = 0.70, F = 18.19, r(LOO)(2) 0.71, r(PRESS)(2) against 16 external test inhibitors = 0.60). Three orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least three binding modes accessible to ligands within CaMKII delta binding pocket. Receiver operating characteristic (ROC) curves analysis established the validity of QSAR-selected pharmacophores. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute (NCI) list of compounds. In silico screening identified nanomolar and low micromolar inhibitors. The most potent hits exhibited IC50 values of 20 and 82 nM. The best pharmacophoric model (Hypo8/31) was employed to guide the synthesis of novel triazine-based CaMKII delta inhibitors, of which the most potent illustrated an IC50 value of 154 nM against CaMKII delta. (C) 2011 Elsevier Ltd. All rights reserved.